DESCRIPTION: (Applicant's Abstract) A growing number of polydrug abusers self-administer cocaine and heroin together, a combination commonly referred to as a "speedball". It has been reported that speedball abusers are more likely to fail in treatment, exhibit more severe psychopathology, and are at higher risk for contracting AIDS than either cocaine or heroin abusers. Despite the prevalence and detrimental consequences of speedball abuse, relatively little is known about its pharmacological basis or treatment. Recent studies have found enhanced effects of cocaine-opioid combinations compared to the effects of the individual drugs in both humans and nonhuman primates. Our proposed research will use established and novel primate models of drug abuse to identify pharmacological mechanisms underlying the enhanced effects of speedball mixtures and to evaluate candidate pharmacotherapies for speedball abuse. In rhesus monkeys trained to discriminate i.v. injections of either heroin or cocaine from vehicle, we will quantify the degree to which the effects of speedball combinations are enhanced compared to those of cocaine or heroin alone, determine the contribution of m and d-opioid and D1 and D2 dopamine receptor mechanisms using selective agonists and antagonists as pharmacological probes, and evaluate candidate pharmacotherapies that modulate the effects of both cocaine and heroin, and thus may interact uniquely with speedball mixtures. In monkeys trained to self-administer either heroin or cocaine under a progressive-ratio schedule of i.v. drug injection, we will use a conceptually similar approach to determine the extent to which the reinforcing potency and effectiveness of speedball combinations are enhanced compared to the individual drugs, characterize opioid and dopamine mechanisms in speedball self-administration, and evaluate candidate medications to reduce speedball abuse. Finally, using a novel primate model of drug relapse, we will determine the degree to which reinstatement of extinguished heroin-seeking or cocaine-seeking behavior is modified by speedball combinations, characterize opioid and dopamine receptor mechanisms in the relapse-inducing effects of speedballs, and evaluate candidate medications for relapse prevention. Overall, the proposed research will provide fundamental information about the pharmacological basis for and potential treatment of speedball addiction.